This application is a 371 of PCT/EP99/05171 filed on Jul. 20, 1999.
The present invention relates to compounds, or pharmaceutical compositions thereof, for systemic and non systemic use, to be employed in the respiratory system pathology treatment with or without infective etiopathogenetic basis, specifically chronic pulmonary diseases (chronic obstructive pulmonary diseases (COPD)), such as asthma, bronchitis, emphysema, thromboembolism with lower side effects compared with the drugs at present used for the treatment of these pathologies.
It is known in the art that for the treatment of these pathologies the most used products are Salbutamol, Salmeterol, etc. See for instance the volume xe2x80x9cTextbook of Therapeutics xe2x80x94Drugs and Disease Managementxe2x80x946th Edition 1996xe2x80x9d page 685. These products are effective but have the drawback to give side effects in particular towards the cardiovascular apparatus. Said products must be administered with caution to patients suffering from cardiovascular pathologies.
Other products used in these pathologies as such or as coadjuvants of other medicines are for instance Ambroxol and Bromhexine, the administration of which is accompanied also by the presence of side effects for the gastrointestinal apparatus, such as burnings and gastric sensitiveness.
The need was felt to have available compounds and their pharmaceutical compositions, effective in the treatment of respiratory system pathologies, combined with lower side effects for the cardiovascular apparatus and/or the gastrointestinal apparatus.
The Applicant has unexpectedly and surprisingly found specific compounds and compositions thereof solving the above mentioned technical problem.
It is an object of the present invention nitrate salts of compounds, or their pharmaceutical compositions, to be used for the treatment of respiratory system pathologies, specifically chronic pulmonary diseases (chronic obstructive pulmonary diseases (COPD)), such as asthma, bronchitis, emphysema, thromboembolism, infective pulmonary diseases, said compounds being characterized in that they contain at least a reactive group capable to be salified with nitric acid, said compounds being selected from the following ones:
Salbutamol having formula (I) 
Cetrezin having formula (II) 
Loratadine having formula (III) 
Terfenadine having formula (IV) 
Emedasine having formula (V) 
Ketoatifen having formula (VI) 
Nedocromil having formula (VII) 
Ambroxol having formula (VIII) 
Bromhexine having formula (IX) 
Dextromethorphan having formula (X) 
Dextrorphan having formula (XI) 
Metronidazole having formula (XII) 
Isoniazid having formula (XIII) 
Erythromycin having formula (XIV) 
Acyclovir having formula (XV) 
Pyrazinamide having formula (XVI) 
The preferred compounds are Salbutamol, also known as Albuterol, Cetrezin, Emedastine, Ambroxol.
The nitrate salts of the present invention can be obtained also by using the above mentioned compounds, which optionally contain one or more xe2x80x94ONO2 groups covalently bound to the molecule by one of the following bivalent binding bridges:
YO wherein Y is a C1-C20 alkylene linear or branched when possible, preferably from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene from 5 to 7 carbon atoms;
Y1 selected from: 
xe2x80x83wherein n3 is an integer from 0 to 3; 
xe2x80x83wherein nfxe2x80x2 is an integer from 1 to 6 preferably from 2 to 4; 
xe2x80x83wherein R1f=H, CH3 and nf is an integer from 1 to 6; preferably from 2 to 4.
These compounds containing a xe2x80x94ONO2 group covalently bound to the molecule by means of one of the above indicated bivalent binding bridges, are prepared as described in the patent application WO 95/30641 in the name of the Applicant, herein incorporated by reference.
In the compositions according to the present invention also one or more isomers (optical isomers included), when available, of the above described compounds, can be used.
Examples of isomers are cis-, trans-, optical isomer D and L or the racemic, enantiomer. In general one isomeric form has higher activity with respect to the other, e.g. D form with respect to L form or vice versa.
The salts of the invention contain at least one nitrate ion mole/mole of the precursor. Preferably the ratio between the moles of nitrate ion and those of the precursor is unity; salts with a higher molar ratio can be obtained when in the molecule there are other amine groups basic enough to form a ionic bond with the nitrate anion.
The salts of the present invention are formulated in the corresponding pharmaceutical compositions according to the known techniques in the field, together with the usual excipients; see for instance the xe2x80x9cRemington""s Pharmaceutical Sciences 15a Ed.xe2x80x9d volume.
The precursors of the salts belonging to the above mentioned classes are prepared according to the methods described in the Merck Index 14a Ed., herein incorporated by reference.
The salts of the present invention are obtainable according to one of the following methods.
If the precursor to be used to form the salt according to the invention is available as a free base, or as a corresponding salt, both soluble in an organic solvent preferably not containing hydroxyl groups in the molecule, such as for example acetonitrile, ethyl acetate, tetrahydrofuran, etc., the nitrate salt is prepared by dissolving the substance or its salt in said solvent at a concentration preferably equal or higher than 10% w/v, and then adding the requested amount of concentrated nitric acid, preferably diluted before addition in the same solvent used formerly to dissolve the compound, preferably cooling the mixture during and after said addition at temperatures between 20xc2x0 C. and 0xc2x0 C., recovering the obtained product by filtration and optionally washing the solid with the same chilled solvent.
When the precursor or its available salt are slightly soluble in the above mentioned solvent, an hydroxylated solvent is added to said solvent to improve solubility. Examples of such hydroxylated solvent are methyl alcohol, ethyl alcohol and water. Precipitation can be accelerated by diluting with an a polar solvent after nitric acid addition.
When the precursor is salified with an hydrogen halogenide, the salt with nitric acid can be prepared by adding silver nitrate to the solution of the halogenide in the above solvent. After filtering off silver halogenide, the solution is concentrated and cooled to recover the nitrate salt by precipitation.
Starting from a salt of the precursor wherein the anion is different from chloride it is however preferable to treat an aqueous solution of said salt with a saturated solution of carbonate or bicarbonate sodium or potassium salt, or with a sodium or potassium hydroxide diluted solution, then extracting the aqueous phase with a suitable organic solvent (for example halogenated solvents, esters, ethers), dehydrating and then evaporating the organic solution, dissolving the thus obtained residue in the above mentioned solvents which do not contain hydroxyl groups, e.g. acetonitrile, or in a mixture of said solvent with an hydroxylated solvent, and then following the aforementioned described preparation methods.
The salts and compositions of the present invention can be used for systemic administration, for example they can be administered by oral route, such as for expectorants; by intramuscular, intravenous route, etc.; or they can be used for non-systemic administrations, for example as aerosols or topical applications. In general the salts of the invention are used for the same therapeutical applications of the precursors.
The nitrate salts of the invention have increased general safety in the confront of the precursors.
The administered doses are those typical of the precursors; however since the products of the invention show a therapeutic effectiveness superior to that of the precursors, they can be used also at doses higher than those of the precursors without giving side effects.
Other applications of the invention products are as tokolitics (antispasmodic), for example uterine musculature antispasmodics, intestinal musculature antispasmodics; antihistamine (antiallergics) for example for ophtalmic applications; anticough, antibacterians for infective respiratory diseases. They can be administered by systemic or non systemic route, as indicated above, or also in the form of ophthalmic compositions, such as collyria, etc.